By interrogating the human genome, we’ve designed therapies that address the root cause of genetic disease. That’s a guiding principle for how we approach our research at 澳门正规博彩十大排行平台, and nowhere is that more true than in our work researching gene therapy. As part of our commitment to expanding our technical expertise, 澳门正规博彩十大排行平台正在研究基因治疗的许多方面，以更好地了解这种突破性治疗方法的各个方面，这对科学界来说仍然是一个挑战. Learn more about that in our newest publication in Nature Medicine. But first, we’re excited to feature Sylvia Fong and Soumi Gupta, 澳门正规博彩十大排行平台的两位科学家渴望与澳门正规博彩十大排行平台分享更多关于基因治疗研究的前沿.

Sylvia and Soumi, thank you so much for joining us today! Can you briefly introduce yourselves and describe your roles at 澳门正规博彩十大排行平台?

Soumi Gupta: I’ve been at 澳门正规博彩十大排行平台 for a little bit over six years. Currently, I lead the clinical immunology group, 澳门正规博彩十大排行平台的主要职责是描述对澳门正规博彩十大排行平台潜在疗法的免疫反应, their impacts on safety and efficacy, 以及可以做出哪些调整来改善每种候选药物的风险/收益概况.

Sylvia Fong: I’ve been with 澳门正规博彩十大排行平台 almost 9 years. 我觉得我在这里有过一些生活:我被带到valoccogene roxaparvovec团队工作, on our investigational gene therapy for hemophilia A, 在那里我负责开发临床前和临床研究的检测方法. Now I’m in a different part of research & development, focused on earlier research, 但我继续与基因治疗研究团队合作，试图回答与AAV基因治疗相关的问题.

You both have a lot of impact on what we’re doing in AAV gene therapy. Can you tell us more about the different studies you’re working on in that area?

SF:生物arin团队目前在AAV基因治疗研究的六个领域进行了大约58项正在进行的研究，科学界和患者倡导团体对此有很多疑问. These focused areas are eligibility, predictability/variability, durability, dependency on prophylaxis, safety, and re-dosing. Redosing is an emerging area of research, but we strive for staying at the fore of all potentially relevant areas of research.

SG: In my team, 澳门正规博彩十大排行平台正试图了解对AAV的免疫反应在这些区域中所起的作用，以及澳门正规博彩十大排行平台如何克服它. Regarding eligibility, 目前的招募主要局限于那些先前对AAV (AAV5)类型没有免疫力的患者，AAV5被用作治疗基因的载体. 因此，澳门正规博彩十大排行平台在生物分析科学领域的合作伙伴与另一个合作伙伴合作开发了一种辅助诊断方法，以帮助筛查患者的免疫力. 这是有趣的，因为它可能对基因治疗所针对的所需蛋白质的表达有影响.

Ultimately though, 澳门正规博彩十大排行平台正试图了解影响表达的已存在免疫的重要决定因素，以帮助澳门正规博彩十大排行平台确定是否有一部分已存在免疫的患者可以安全地接受AAV基因治疗. 澳门正规博彩十大排行平台还从事非临床研究，以评估可能使澳门正规博彩十大排行平台克服先前存在的免疫的干预措施. Additionally, 澳门正规博彩十大排行平台正试图了解免疫反应是否以及如何在患者的蛋白质表达变化中发挥作用. Is variability due to an immune response? And if so, an immune response to what, specifically?

SF: Yes. 澳门正规博彩十大排行平台真正想要了解的是个体患者的哪些因素可能导致表达的可变性和持久性. Their immune responses are one component of it, but there are many others. That’s really what my group is focusing on. 澳门正规博彩十大排行平台的信念是，一旦你确定了机制，你就可以对此采取措施.

With the study we just published in Nature Medicine, we wanted to find out how long the AAV-delivered transgene would persist in the liver, 以及评估安全性和导致反应因人而异的因素. 澳门正规博彩十大排行平台通常依靠临床数据来了解安全性和有效性，澳门正规博彩十大排行平台很高兴看到大量来自澳门正规博彩十大排行平台试验的数据, 但是澳门正规博彩十大排行平台仍然有很多生物学上的问题关于基因疗法的命运，一旦它到达肝脏，澳门正规博彩十大排行平台只能通过直接分析肝脏组织来回答. Liver biopsy data are difficult to capture due to the invasiveness of the procedure, 但由于澳门正规博彩十大排行平台的研究参与者的利他主义和他们渴望为这种治疗方案的知识体系做出贡献, we had the rare and exciting opportunity to analyze biopsy samples. Our analyses revealed the liver cells did contain the therapeutic DNA, with higher levels in participants who received higher doses, as we’d expect.

SG: Yes. And to speak to the safety piece, 在AAV基因治疗领域存在的一个教条是，针对AAV衣壳的t细胞反应导致ALT和AST升高，并且已观察到转基因表达降低. We’ve been studying this extensively, both preclinically and in clinic, and we found that contrary to the T-cell hypothesis, 澳门正规博彩十大排行平台不一定看到细胞毒性t细胞反应和ALT/AST升高之间的明确联系. So, we are trying to, as Sylvia said, go back and ask what is causing those elevations, if not T-cells? There’s a bigger mechanistic story here that we’re trying to understand and address.

Once you identify the mechanisms at play, what do you do next?

SG: In general terms, 你会开始战略性地思考改变免疫反应的最安全的选择, it’s trigger, or both. Our prophylactic steroid study is one example of that. Going forward, 澳门正规博彩十大排行平台通过临床免疫学研究学到的东西可以在许多方面帮助指导治疗发展, to continue to give us the best chances of improving clinical outcomes.

Is that what happens in 澳门正规博彩十大排行平台’s Center of Technology?

SG: Yes! We partner with the Center of Technology closely. One example is our work with the Flow Core group, 这有助于澳门正规博彩十大排行平台使用流式细胞术来测试假设，即使用肝脏定向基因疗法可以诱导使用因子VIII替代疗法的患者产生免疫耐受, which is another area of research we are pursuing. We’re also looking at various assays to monitor and measure cytokines, 因为澳门正规博彩十大排行平台很难想出一种能够在临床上使用的检测方法，它足够敏感，足够特异.

总而言之，经过这么长时间，你对基因治疗的看法改变了吗?

SG: Yes, tremendously. We are still just scratching the surface, but I think that we are absolutely at the forefront of the gene therapy. 我不相信有任何其他公司在试图理解机制方面所做的工作接近澳门正规博彩十大排行平台所做的工作量, 是什么影响了不同的方面比如安全性，有效性和可变性，持久性.

SF: There are challenges and unknowns that need to be addressed with gene therapy, 但我认为澳门正规博彩十大排行平台在过去的9年里做了很多，学到了很多，澳门正规博彩十大排行平台在AAV基因治疗方面处于领先地位. 我相信基因疗法有可能改变许多患有严重遗传疾病的人的生活. 基因治疗成功的关键是不断投资于理解和改进技术，以便澳门正规博彩十大排行平台能够更好地为患者服务.

感谢你们对科学的开创性贡献，也感谢你们如此慷慨地投入时间.